Targeted overexpression of human alpha-synuclein triggers microglial activation and an adaptive immune response in a mouse model of Parkinson disease.

Academic Article

Abstract

  • Microglial activation and adaptive immunity have been implicated in the neurodegenerative processes in Parkinson disease. It has been proposed that these responses may be triggered by modified forms of alpha-synuclein (alpha-SYN), particularly nitrated species, which are released as a consequence of dopaminergic neurodegeneration. To examine the relationship between alpha-SYN, microglial activation, and adaptive immunity, we used a mouse model of Parkinson disease in which human alpha-SYN is overexpressed by a recombinant adeno-associated virus vector, serotype 2 (AAV2-SYN); this overexpression leads to slow degeneration of dopaminergic neurons. Microglial activation and components of the adaptive immune response were assessed using immunohistochemistry; quantitative polymerase chain reaction was used to examine cytokine expression. Four weeks after injection, there was a marked increase in CD68-positive microglia and greater infiltration of B and T lymphocytes in the substantia nigra pars compacta of the AAV2-SYN group than in controls. At 12 weeks, CD68 staining declined, but B- and T-cell infiltration persisted. Expression of proinflammatory cytokines was enhanced, whereas markers of alternative activation (i.e. arginase I and interleukins 4 and 13) were not altered. Increased immunoreactivity for mouse immunoglobulin was detected at all time points in the AAV2-SYN animals. These data show that overexpression of alpha-SYN alone, in the absence of overt neurodegeneration, is sufficient to trigger neuroinflammation with both microglial activation and stimulation of adaptive immunity.
  • Keywords

  • Animals, Antigens, CD, Antigens, Differentiation, Myelomonocytic, Brain, Chemotaxis, Leukocyte, Cytokines, Disease Models, Animal, Dopamine, Genetic Vectors, Humans, Immune System Phenomena, Immunoglobulins, Lymphocyte Activation, Male, Mice, Mice, Inbred C57BL, Microglia, Nerve Degeneration, Parkinson Disease, Substantia Nigra, Transfection, alpha-Synuclein
  • Digital Object Identifier (doi)

    Author List

  • Theodore S; Cao S; McLean PJ; Standaert DG
  • Start Page

  • 1149
  • End Page

  • 1158
  • Volume

  • 67
  • Issue

  • 12